Preliminary response to Tislelizumab plus chemotherapy drugs in patient with periampullary carcinoma: a report of one case and a literature review

Periampullary carcinoma is a malignant gastrointestinal tumor originating from the head of the pancreas, distal bile duct, duodenum, or the ampulla of Vater. Currently, surgery remains the primary treatment option, yet the postoperative recurrence rate remains high. Chemotherapy is the main approach for controlling postoperative recurrence. Histologically, periampullary carcinoma is categorized into two types: intestinal (IN) and pancreaticobiliary (PB) subtype. Each subtype requires different therapeutic approaches, with the PB type primarily treated with gemcitabine and the IN type with 5-FU. Despite these options, patient outcomes are still unsatisfactory. In recent years, the feasibility of immunotherapy in tumor treatment has been increasingly evidenced, although research on its efficacy in periampullary carcinoma treatment is still limited. In this report, we present a case of a periampullary carcinoma patient who experienced recurrence and metastasis after undergoing radical pancreatoduodenectomy and receiving gemcitabine-based chemotherapy post-surgery. Through next-generation sequencing (NGS), we identified high expression levels of programmed cell death-ligand 1 (PD-L1) with a combined positive score (CPS) of 35, high tumor mutation burden (TMB-H), and high microsatellite instability (MSI-H) in this patient. Therefore, we implemented a combination therapy using Tislelizumab and chemotherapy. According to the latest follow-up, the tumors are effectively controlled. Our utilization of immunotherapy combined with chemotherapy holds significant implication for the treatment of periampullary carcinoma.


Introduction
Periampullary carcinoma is a malignant tumor that originates approximately 2.0 cm the ampulla of Vater, which can influence to the pancreatic head, the ampulla of Vater, the distal common bile duct and duodenum (1).The majority of these tumors are adenocarcinomas.Currently, surgical resection remains the main therapy option to improve long-term survival and is practicable in approximately 50% of ampullary cancer cases (2).Nonetheless, the overall survival time is still limited due to the high risk of recurrence and metastasis (3).Therefore, adjuvant therapy (AT), such as chemotherapy, is recommended for improving the long-term survival (4).
At present, immunotherapy has emerged as a promising clinical strategy for treatment.In addition, immunotherapy has been incorporated into clinical guidelines for various cancers, including non-small cell lung cancer, esophageal cancer and colorectal cancer (5-7).The assessment of tumor mutation burden (TMB), microsatellite instability (MSI), deficiency of mismatch repair (dMMR), and the expression of PD-L1 are important criteria for determining the individual suitability of immunotherapy (8).However, the prognosis of immunotherapy for patients with periampullary carcinoma remains limited.
Here, we report our experience in treating a periampullary carcinoma patient with high PD-L1 expression, high tumor mutation burden (TMB-H) and high microsatellite instability (MSI-H), who received a combination of Tislelizumab and chemotherapy.The patient demonstrated positive therapeutic outcomes and exhibited acceptable treatment tolerance.By providing comprehensive clinical evaluations and relevant patient histories, we aim to contribute valuable insights into the application of immunotherapy in periampullary carcinoma.
On May 30, 2022, the patient underwent radical pancreaticoduodenectomy and recovered well without any complications.The postoperative pathological report confirmed a medium-poorly differentiated adenocarcinoma of the duodenum, classified as the PB type (Figure 1B).Metastasis was found in 4 of 15 lymph nodes.The patient received six cycles of gemcitabine (1.6g/d, d1, d8, d15, q4w) + capecitabine (2g/d, d1-d21, q4w) as postoperative conventional chemotherapy from August 2022 to November 2022.
Based on these results, we decided to administrate chemotherapy combined with immunotherapy for the patient.Between February 2023 and July 2023, the patient received six cycles of gemcitabine (1.6g/d, d1, d8, q3w) + S-1 (100mg/d, d1-d14, q3w) + Tislelizumab (200mg/d, d1, q3w) (Figure 3).During the medication, the patient did not have any discomfort and no drug side effects were noted.As of May 2023, CECT indicated that the patient's tumors shrank 79.5% (from 26.30 cm 3 to 5.40 cm 3 , PR) (Figures 4A, B).The latest CECT report in January 2024 showed the patient was in stable condition, which indicated complete response (CR) (Figures 4C, D).At present, surgical resection is the first for the periampullary carcinoma treatment (9, 10), with the postoperative survival rates varying among periampullary carcinoma subtypes at different anatomical locations.Adjuvant chemotherapy is commonly used to improve long-term survival (9, 11), as the general 5-year survival rates for different subtypes of ampullary carcinoma after surgery are between 33% to 68%.Based on heterogeneous mucosal origin, periampullary cancer can be divided into intestinal (IN) and pancreaticobiliary (PB) subtype.The PB type is associated with significantly worse outcomes, with a median overall survival (OS) of In recent years, the introduction of tumor immunotherapies has revolutionized the cancer treatment landscape.For example, some PD-1 inhibitors, such as Tislelizumab, are being tested its efficacy in clinical trials.In a phase 1/2 trial of Tislelizumab involving 251 Chinese patients with advanced-stage solid tumors who had previously failed anti-tumor treatment, 18% of the cohorts achieved a confirmed response.Notably, patients with nasopharyngeal carcinoma (81%), non-small cell lung cancer (54%), renal cell carcinoma (52%), MSI-H/dMMR solid tumors (50%), and hepatocellular carcinoma (50%) exhibited a favorable clinical benefit rate (CBR ≥50%, defined as the sum of complete response, partial response, and stable disease) (14).In another study involving 15 patients with recurrent or metastatic oral squamous cell carcinoma demonstrated a 40% partial response following treatment with a combination of Tislelizumab and nimotuzumab (15).Furthermore, a study focused on contrasting the effectiveness of Tislelizumab versus chemotherapy in patients with advanced or metastatic esophageal squamous cell carcinoma reported a higher overall response rate in Tislelizumab treatment of 20.9% compared with the chemotherapy of 9.8% (16).
The cellular origin of periampullary carcinoma of PB type may be pancreatic or biliary duct cells.Although immunotherapy has shown limited progress in pancreatic cancer, it has achieved some advancements in biliary tract tumors.Recent large-scale clinical trials investigating the combination of chemotherapy with immunotherapy in biliary cancer have yielded promising results.For instance, the KEYNOTE-966 trial, which involved 1564 patients with locally advanced or metastatic biliary cancer worldwide, demonstrated that the addition of pembrolizumab to gemcitabine and cisplatin significantly improved overall survival (17).Similarly, the TOPAZ-1 study, which enrolled 685 patients with advanced biliary tract cancer, reported that the addition of durvalumab to gemcitabine and cisplatin led to a significant improvement in overall survival compared to the placebo group (18).Furthermore, research conducted by Do-Youn Oh et al. revealed that combining gemcitabine and cisplatin with durvalumab may confer a survival benefit compared to either treatment modality alone (19).These findings underscore the potential synergistic effects of chemotherapy and immunotherapy in improving outcomes for patients with biliary cancer.
According to current clinical studies, immunotherapy has also shown therapeutic efficacy in some cases of periampullary carcinoma.For instance, a case reported by Pothuri et al. described a 59-year-old female who was diagnosed as Lynch's syndrome and moderately differentiated ampullary adenocarcinoma of PB type with metastasis of adjacent lymph nodes.The patient was determined as MSI-H, TMB-H as well as dMMR type with high PD-L1 expression by the results of NGS and IHC.The patient received three-week administration of four consecutive cycles of nivolumab (1mg/kg) combined with Ipilimumab (3mg/kg) before surgical resection, resulting in a complete pathological response and tumor downstaging from 7.5cm to 5.2cm, which created a favorable prerequisite for further resection.Therefore, the team

FIGURE 1 CECT
FIGURE 1 CECT and pathological result of the patient before and after surgery.(A) Tumor condition at first CECT scan.(B) The results of pathological biopsy.(C, D) Tumor conditions after six cycles of gemcitabine + capecitabine.CECT, contrast-enhanced computed tomography.
16.1 months compared to 115.5 months for the IN type according to the study of Chang D.K et al. (p <0.001) (12).Different chemotherapy regimens are often used for each subtype, with 5-FU based regimens used for IN type and gemcitabine-based regimens used for PB type (10, 13).Although it is generally accepted that chemotherapy can benefit patients after surgery, whether the utilization of chemotherapy is solidly necessary still remains controversies because of the obvious heterogeneity of the therapeutic effectiveness among patients.

FIGURE 3
FIGURE 3Timeline of the patient's treatment progress.

FIGURE 2 The
FIGURE 2 The IHC of the patient's sample.(A) Negative control.(B) Positive control.(C) The test result of the patient.IHC, immunohistochemistry.